This application is a continuation of International Application PCT/KR 00/00030, with an international filing date of Jan. 18, 2000, now abandoned.
1. Field of the Invention
The present invention relates to novel antifungal azole derivatives having a fluorinated vinyl group, a process for preparing same and an antifungal composition containing same as an active ingredient.
2. Description of the Prior Art
A number of antifungal compounds have been developed for treating diseases caused by fungal infection and examples by currently available antifungal drugs include such azole derivatives as Fluconazole of Pfizer (GB Pat. No. 2,099,818, U.S. Pat. No. 4,404,216), Itraconazole of Janssen (U.S. Pat. No. 4,267,179, EP Patent Publication No. 6,711) and Voriconazole of Pfizer (EP Patent Publication No. 440,372, U.S. Pat. No. 5,278.175).
However, a long-term use of the above drugs may cause side effects such as liver damage and there has emerged a renewed interest in developing a more active and less toxic antifungal drug, as an ever increasing number of people are afflicted with such diseases as AIDS (acquired immune deficiency syndrome), cancer and diabetes, and become vulnerable to fungal infection.
Recently, a number of new azole derivatives have been developed by Janssen (see German Patent No. 2,804,096, U.S. Pat. Nos. 4,144,346 and 4,223,036, and PCT Publication No. WO95/08,993), Schering (see PCT Publication No. WO95/17,407 and WO93/09,114), Takeda(see EP Publication No. 421,210) and YuhanCorporation(see PCT Publication No. WO95/025,107) however, these antifungal compounds exhibit lower antifungal activities and narrower antifungal spectra in comparison with the conventional drugs.
The present inventors have endeavored to develop compounds having high antifungal activity against a wide spectrum of pathogenic fungi; and have unexpectedly found that a new class of azole derivatives having a fluorinated vinyl group exhibit excellent antifungal activities and low toxicity.
Accordingly, it is aprimary object of the present invention to provide a novel compound which is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi including Candida albicans, Torulopsis, Cryptoccocus, Aspergillus, Trichophyton and Fluconazole-resistant Candida alhicans, and also in toxicity.
It is another object of the present invention to provide a process for the preparation of said compound.
It is a further object of the present invention to provide an antifungal composition containing said compound.
In accordance with one aspect of the present invention, there is provided a novel azole derivative of formula (I) or a pharmaceutically acceptable salt thereof: 
wherein:
X is CH or N; 
Y is O,
R1 and R2 are each independently F or Cl;
R3 is a thiophenyl, naphthyl, or phenyl group, the phenyl group being optionally substituted with one or more substituents selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, methylenedioxy and halogen; and
R4 is H or trifluoromethyl.
Among the compounds of the present invention, preferred are those wherein YisO; R3 isaphenyl groupoptionally substituted with one or more substituents selected from the group consisting of Cl, F and Br.
Further, another preferred are those wherein X is CH; Y is O; R3 is methylphenyl; and R4 is H.
The novel azole derivatives substituted carrying a fluorinated vinyl group of formula (I) of the present invention may be prepared by a process which comprises reacting a compound of formula (II) with a fluorinated vinyl compound of formula (III) in the presence of a base as shown in Reaction Scheme 1. 
wherein, X, Y, R1, R2, R3 and R4 have the same meanings as defined in formula (I).
In the above reaction, the compounds of formulae (II) and (III) may be used in equimolar amounts, and the base, in 1 to 2 molar amount.
Further, the solvent which can be used in the present invention includes a typical organic solvent, e.g., benzene, toluene, tetrahydrofuran, acetone, acetonitrile, dichloromethane, dimethylformamide and dimethylsulfoxide and it also includes an organic solvent mixed with water.
The base which can be used in the present invention includes an inorganic base (e.g.: sodium hydride, potassium hydride, potassium t-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate) and an organic base (e.g.: triethylamine and pyridine).
The reaction temperature may range from a room temperature to 100xc2x0 C. and the progress of the reaction is conveniently followed by measuring the disappearance of the compound of formula (II) with thin layer chromatography (TLC).
The compound of formula (II) is represented by the compounds of formulae (II-a), (II-b) and (II-c) depending on the definition of the substituent Y. 
wherein, X, R1 and R2 have the same meanings as defined above.
A compound of formula (II-a) may be prepared by a conventional method(see Heeres, J. et al., J. Med. Chem., 22(8), 1003(1979)) as shown in Reaction Scheme 2: 
wherein, X, R1 and R2 have the same meanings as defined above.
In Reaction Scheme 2, i) the carbonyl group of a compound of formula (II-a-5) is protected to form a compound of formula (II-a-4); ii) the compound of formula (II-a-4) is brominated to form a compound of formula (II-a-3) (see Levene, P. A., Org. Syn. Coll., 2, 88 (1943)); the compound of formula (II-a-3) is benzoylated and recrystallized to form a compound of formula (II-a-2) (see Wheeler, T. S., Org. Syn. Coll., 4, 478(1943), and Szeja, W., Synthesis., 821 (1979)); and the compound of formula (II-a-2) is subjected to a substitution reaction to form a compound of formula (II-a-1), which is, in turn, debenzoylated to form a compound of (II-a)(see Mashimo, K. et al., Tetrahedron, 26, 803 (1970)).
Since the compound of formula (II-a) has two chiral carbons, it is obtained as a mixture of four stereoisomers, a cis- and trans-type diastereomers each of which is composed of two enantiomers. In the present invention, the cis type diastereomer is separated in one of the subsequent reaction steps to form a compound of formula (II-a).
For example, 2-bromomethyl-2-(2,4-dichlorophenyl)-4-phenylcarbonyloxymethyl-1,3-dioxolane obtained from the reaction of 2-bromomethyl-2-(2,4-dichlorophenyl)-1,3-dioxolan-2-yl methanol (i.e., the compound of formula (II-a-3) wherein R1 and R2 are Cl) with benzoyl chloride is subjected to recrystallization to separate the cis diastereomer having a melting point of 115xc2x0 C. in the form of a colorless crystal which is used in the next reaction, as in Reaction Scheme 2.
Further, in case of 2-bromomethyl-2-(2,4-difluorophenyl)-4-phenylcarbonyloxymethyl-1,3-dioxolane obtained from the reaction of 2-bromomethyl-2-(2,4-difluorophenyl)-1,3-dioxolan-2-yl methanol(i.e., the compound of formula (II-a-3) wherein R1 and R2 are F) with benzoyl chloride, it is converted into 2-(2,4-difluorophenyl)-2-(1H-1-imidazolyl-methyl)-4-phenylcarbonyloxymethyl-1,3-dioxolane, which is subjected to recrystallization to separate the cis form(i.e., a compound of formula (II-a-1)) having a melting point of 136xc2x0 C., as shown in the following Reaction Scheme 3. 
wherein, X has the same meaning as defined above.
In the present invention, cis isomers of formulae (II-a) and (II-b) and (II-c) are used.
A compound of formula (II-b) may be prepared by the method described in Heeres, J. et al., J. Med. Chem., 26 (4). 611 (1983), i.e., by the process shown in Reaction Scheme 4 which comprises the steps of conducting a sulfonation reaction of a compound of formula (II-a) (see Furst A. et al., Helv. Chem. Acta. 30. 1454 (1947)), substitution and debenzylation (see Heathcock, C. H. et al., J. Amer. Chem. Soc., 93. 1746 (1971)). 
wherein, X, R1 and R2 have the same meanings as defined above.
An amine of formula (II-c) which can be used as a starting material in preparing the compound of formula (I) may be prepared by the method described in Heeres, J. et al., J. Med. Chem., 27 (7). 894 (1984), i.e., by the process shown in Reaction Scheme 5 which comprises the steps of conducting a substitution reaction of a compound of formula (II-b-2) to form a compound of formula (II-c-1) and hydrolysis of the compound of formula (II-c-1). 
wherein, X, R1 and R2 have the same meanings as defined above.
The fluorinated vinyl compound of formula (III) is represented by the compounds of formulae (III-a) and (III-b) depending on the definition of the substituent R4. 
wherein, R3 has the same meaning as defined in formula (I) above.
Among the fluorinated vinyl compound of formula (III), the compound of (III-a) wherein R4 is H may be prepared by a conventional method (see Herkes, F. E. et al., J. Org. Chem., 32, 1311 (1967)), e.g., by the process shown in Reaction Scheme 6 which comprises the steps of conducting a Grignard reaction of the halogenated compound of formula (III-a-4), reduction, chlorination and dehalogenation. Further, the compound of (III-b) wherein R4 is CF3 may be prepared by a Wittig reaction using a ketone of formula (III-a-3) as a starting material as shown in Reaction Scheme 6 (see Herkes, F. E. et al., J. Org. Chem., 48, 917 (1983)). 
wherein, R3 has the same meaning as defined in formula (I) above and Z is a halogen such as Br and Cl.
The compound of formula (I) of the present invention has a double bond in its vinyl moiety, and thus, Z(zusammen) and E(entgegen) isomers may co-exist. Further, due to the chiral carbons at 2- and 4-position of the dioxolane ring, the compound of formula (I) may exist in the form of either (2R,4S) or (2S,4R) stereoisomers.
In case of the compound of formula (I-1) wherein the chiral carbons have the configuration of (2R,4S) and X, Y, R1, R2 and R3 have the same meanings as defined above, the compound is an E isomer when R4 is H, while the compound is a Z isomer when R4 is CF3. 
In case of the compound of formula (I-2) wherein the chiral carbons have the configuration of (2R,4S) and X, Y, R1, R2 and R3 have the same meanings as defined above, the compound is a Z isomer when R4 is H, while the compound is an E isomer when R4 is CF3. 
Further, in case of the compound of formula (I-3) wherein the chiral carbons have the configuration of (2S, 4R) and X, Y, R1, R2 and R3 have the same meanings as defined above, the compound is an E isomer when R4 is H, while the compound is a Z isomer when R4 is CF3. 
In case of the compound of formula (I-4) wherein the chiral carbons have the configuration of (2S,4R) and X, Y, R1, R2 and R3 have the same meanings as defined above, the compound is a Z isomer when R4 is H, while the compound is an E isomer when R4 is CF3. 
In practicing the present invention, the compound of formula (I) wherein R4 is H is obtained mainly in the form of a mixture of E-isomers((I-1) and (I-3)), Z-isomers((I-2) and (I-4)] being a minor product. When R4 is CF3, the reaction mixture contains mainly Z-isomers((I-1) and (I-3)), with a minor amount of E-isomers((I-2) and (I-4)].
The compound of formula (I) exhibit excellent antifungal activity against a wide spectrum of pathogenic fungi including Candida albicans, Torulopsis, Cryptoccocus, Asperqillus, Trichoohyton and Fluconazole-resistant Candida albicans, as well as fungicidal activities.
The present invention also includes within its scope an antifungal composition comprising one or more of the novel azole derivatives of formula (I) as an active ingredient, in association with pharmaceutically acceptable carriers, excipients or other additives, if necessary.
The pharmaceutical compositions of the present invention may be formulated for administration orally or by injection. The composition for oral administration may take various forms such as tablets and gelatin capsules, which may contain conventional additives such as a diluent (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), a lubricant (e.g., silica, talc, stearic acid or its magnesium and calcium salts and polyethylene glycol). In the tablet form, the composition may further comprise a binder (e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl picolidine) and optionally a disintegrant (e.g., starch, agar and alginic acid or its sodium salt), absorbent, colorant, flavor and sweetener. The composition for injection may be an isotonic solution or a suspension. The inventive pharmaceutical composition may be administered daily. A typical daily dose of the active ingredient ranges from about 1 to 1000 mg/kg, preferably 1 to 200 mg/kg, and can be administered in a single dose or in divided doses, preferably 1 to 3 doses. However, it should be understood that the amount of the active ingredient actually administered should be determined in light of various relevant factors including the condition to be treated, the chosen route of administration, the age and weight of the individual patient, and the severity of the patient""s symptoms; and, therefore, the dosage suggested above should not be construed to limit the scope of the invention in any way.
The compounds of the present invention may be administered simultaneously with one or more other anti-bacterial agent, analgesic, anti-cancer agent and anti-viral agent and the oral formulations and injections can be used simultaneously.